Disulfiram loaded calcium phosphate nanoparticles for enhanced cancer immunotherapy

Abstract

Considering the huge cost and long test periods required for new drug development, repurposing drugs that have already been applied in the clinic as new cancer treatment candidates represents an attractive alternative. Disulfiram (DSF) was originally used to treat alcoholism and has proven to have anticancer effects with the coadministration of copper ions (Cu²⁺). However, the limited water-solubility of DSF and systemic toxicity induced by exogenous Cu²⁺ hinder its practical application. Herein, we constructed pH-responsive lipid-coated calcium phosphate nanoparticles (LCP NPs) co-loaded with Cu²⁺ and DSF. After intravenous injection, those nanoparticles with long blood half-life preferentially accumulate in tumors, followed by the degradation of nanoparticles in response to the acidic tumor microenvironment, subsequently releasing Cu²⁺ and DSF to generate cytotoxic metabolite DTC-Copper complex, bis(diethyldithiocarbamate)-copper (CuET) for tumor treatment. In addition to direct cytotoxicity, the active metabolite CuET could effectively induce immunogenic cell death (ICD) of cancer cells to regulate the immunosuppressive tumor microenvironment, contributing to enhanced immune checkpoint blockade (ICB) therapy in triggering systemic immune responses. This work thus demonstrates the great promises of repurposing the old drug DSF as a new ICD inducer with nano-formulation, to achieve improved synergetic tumor-responsive therapy with low side effects.

Keywords: Chemotherapy; Disulfiram; Immunogenic cell death; Immunotherapy; Nanomedicine.